Compound containing 1,3-benzodioxol structure and preparation method and use thereof

Abstract

The invention provides a compound containing a 1,3-benzodioxol structure and a preparation method and use thereof. The invention discloses a 1,3-benzodioxol derivative as shown in general formula (1). Results of pharmacological experiments indicate that compound (I) of the invention can exert excellent inhibition on both BTK and JAK3 kinases, and can be used to prepare medicines for treating rheumatoid arthritis caused by over-activation of BTK and/or JAK3 pathways. The invention further discloses a preparation method for the 1,3-benzodioxol derivative.

1 . A compound of general formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein X represents N or CH; A represents O, S, —NHCO—, —NHCOCH 2 — or —NHSO 2 —; m represents 0 or 1, and n represents 0 or 1;
 R 1  represents: 
 
       
         
           
           
               
               
           
         
         wherein p represents 0 or 1; R 4  represents H, F, Cl, Br, I, C1-C6 alkyl, CF 3 , OH, C1-C6 alkoxy, OCF 3 , CN, NO 2 , NH 2 , C1-C6 alkylamine, N(CH 3 ) 2 , N(C 2 H 5 ) 2 , NHCOCH 3 , CONH 2 , CONHCH 3 , CONHCH 2 CF 3 , OCH 2 CH 2 OCH 3  and C 6 H 5 , 
       
       
         
           
           
               
               
           
         
       
       and R 4  can be mono-, double- or triple-substituted; Y 1 , Y 2 , Y 3 , Y 4  represent N or C—R 5 , R 5  represents H, F, Cl, Br, I, CH 3 , CF 3 , OH, OCH 3 , OCF 3  or CN; Z represents O, S or N—R 6 , R 6  represents H, CH 3 , C 2 H 5  or cyclopropyl; R 2  represents H, Cl, Br or CN; and R 3  represents H, substituted C1-C6 alkyl, substituted C2-C6 heterocycloalkyl, wherein the substituent is OH, NH 2 , OCH 3 , NHCH 3  or NHCOCH 3 , and the heterocycloalkyl contains a four-, five- or six-membered saturated heterocycloalkyl group with 1-3 atoms of O, N or S. 
     
     
         2 . The compound or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein A represents —NHCO— or —NHSO 2 —; m represents 1, n represents 0; and R 2  and R 3  represent H. 
     
     
         3 . The compound or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein A represents —NHCO— or —NHSO 2 —; m=0, n=1; and R 2  and R 3  represent H. 
     
     
         4 . The compound or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein the compound has the following general structural formula (II): 
       
         
           
           
               
               
           
         
       
       wherein definitions of X and R 1  are the same as those in  claim 1 . 
     
     
         5 . The compound or the pharmaceutically acceptable salt thereof according to  claim 4 , wherein R 1  represents: 
       
         
           
           
               
               
           
         
         wherein R 7  represents H, F, Cl, Br, CHs, t-Bu, CF 3 , CN, OH, OCH 3 , OCF 3 , NH 2 , N(CH 3 ) 2 , N(C 2 H 5 ) 2 , NHCOCH 3 , CONH 2 , CO D NHCH 3 , CONHCH 2 CF 3 , C 6 H 5 , 
       
       
         
           
           
               
               
           
         
       
       R 7  can be mono-, double- or triple-substituted, and R 8  represents H, Cl or CH 3 . 
     
     
         6 . The compound or the pharmaceutically acceptable salt thereof according to  claim 5 , wherein R 7  represents H, Cl, CH 3 , t-Bu, CF 3 , OCH 3 , N(CH 3 ) 2 , N(C 2 H 5 ) 2  or CONHCH 2 CF 3 , R 7  can be mono-, double- or triple-substituted, and R 8  represents Cl. 
     
     
         7 . The compound or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein the compound is I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, or I-34. 
     
     
         8 . The compound or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein the pharmaceutically acceptable salt is an acid addition salt formed by the compound of general formula (I) according to  claim 1  and the following acids: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or ferulic acid. 
     
     
         9 . A pharmaceutical composition, comprising the compound or the pharmaceutically acceptable salt thereof according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         10 . A preparation method for the compound according to  claim 1 , wherein a chemical reaction route is as follows: 
       
         
           
           
               
               
           
         
         where definitions of R 1 , R 2 , R 3 , X, A, m and n are the same as those in  claim 1 . 
       
     
     
         11 . The preparation method according to  claim 10 , further comprising a preparation step of a compound of general formula (III), wherein a chemical reaction route of the step is as follows: 
       
         
           
           
               
               
           
         
       
       Wherein definitions of X, m and n are the same as those in  claim 10 . 
     
     
         12 . The preparation method according to  claim 10 , further comprising a preparation step of a compound of general formula (IV), wherein a chemical reaction route of the step is as follows: 
       
         
           
           
               
               
           
         
       
       wherein A is selected from —NHCO—, —NHCOCH 2 — or —NHSO 2 —, and a definition of R 1  is the same as that in  claim 10 . 
     
     
         13 . A method for inhibiting BTK and/or JAK3, comprising administering to a subject in need thereof an effective amount of the compound or the pharmaceutically acceptable salt thereof according to  claim 1 . 
     
     
         14 . A method for inhibiting BTK and JAK3 dual-target, comprising administering to a subject in need thereof an effective amount of the compound or the pharmaceutically acceptable salt thereof according to  claim 1 . 
     
     
         15 . A method for treating rheumatoid arthritis or B-cell lymphoma, comprising administering to a subject in need thereof an effective amount of the compound or the pharmaceutically acceptable salt thereof according to  claim 1 .